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02.24.10 Lecture 17 - Cell motility The Range of Cell Movement •Velocities of moving cells span more than 4 orders of magnitude • Each cell has evolved the speed and mechanism of its migration to match: •Developmental programs •The cell’s unique energy requirements •The way the cell acquires nutrients • The direction of cell migration “-taxis” -Cell movement according to an environmental cue •Can be an attracting or repelling signal • Kinds of signals • Chemotaxis - soluble factor (molecule or protein) • Haptotaxis - same as chemotaxis, but the signal is immobilize on a surface • Durotaxis - rigidity of the cell’s substrate “-Taxis”, a form of cell signaling 1. Reception of signal 2. Transduction of signal 3. Cellular response Cell motility towards or away from the signal Cellular locomotion is an essential part of life for many organisms Single celled protozoa Dictyostelium iscoideum http://www.youtube.com/watch?v=VWGA7kIeE0Q Cellular locomotion is an essential part of life for many organisms Single celled protozoa Dictyostelium discoideum Mahadeo and Parent, 2006 http://www.youtube.com/watch?v=VWGA7kIeE0Q Cellular locomotion is an essential part of life for many organisms Embryonic development in animals Later Development - Once the neurons have found their home within the cerebral Movements of autonomous cells or cortex they send out axons that stretch specialized cellular structures into other parts of the brain Chemoattractant QuickTime™ and a Photo decompressor are needed to see this picture. arly development - neurons migrating from their point of origin to heir developmental destination QuickTime™ and a Photo decompressor are needed to see this picture. Chemorepellent Cellular locomotion is an essential part of life for many organisms Embryonic development in animals Collective movement of groups of cells How are cohorts of cells able to stay together as they migrate through tissue (also made of cells) and how do they know when (or if) they’re to come apart? Zebrafish cells QuickTime™ and a H.264 decompressor are needed to see this picture. Lecaudey, et al., 2008 8 Cellular locomotion is an essential part of life for many organisms Wound healing and tissue remodeling Cells sense the loss of epithelial integrity (neighbors) which triggers cell motility and gene transcription QuickTime™ and a MPEG-4 Video decompressor are needed to see this picture. Cellular locomotion is an essential part of life for many organisms Immune cells Macrophages and Neutrophils Migrate toward chemical signals from bacteria and other pathogens QuickTime™ and a mpeg4 decompressor are needed to see this picture. Cellular locomotion is an essential part of life for many organisms Immune cells Macrophages and Neutrophils Migrate toward chemical signals from injured, inflamed, and dead tissue (called Necrotaxis) Cellular locomotion is an essential part of life for many organisms Pollen Tube Growth Required to transport nonmotile sperm to ovule tissue QuickTime™ and a Video decompressor are needed to see this picture. Misregulation of cell migration contributes to disease • Congenital birth defects • Chronic inflammatory diseases (asthma & arthritis) • Cancer (metastasis) • Atherosclerosis & heart disease Rolling leukocytes are recruited to sites of injury or inflammation QuickTime™ and a MPEG-4 Video decompressor are needed to see this picture. Atherosclerosis How do cell’s move? Cellular migration is a cycle of 4 processes 1. 2. 3. 4. Polarization of the cell (defining front vs. back) Protrusion of the leading edge Formation of adhesive contacts with the surface De-adhesion and retraction of the trailing edge QuickTime™ and a YUV420 codec decompressor are needed to see this picture. Cell polarity is regulated by signaling molecules that create a “leading edge” and “trailing edge” 1. 2. 3. Membrane receptors (GPCRs, RTKs) detect an asymmetric signal from outside the cell Receptors activate Raslike small G proteins (Rhofamily proteins) Rho-family proteins induce cytoskeletal changes at the leading (Rac, Cdc42) and trailing (Rho) edges of the cell Rho family members are Ras-like proteins that regulate cell morphology and polarity Rho protein localizes to the trailing edge of crawling neutrophils Actin / Rho Signaling during cell polarization Cell polarization requires the orientation and capture of microtubules at the leading edge 2. Protrusion • Protrusion is driven primarily by forces that are produced by actin polymerization • There are 2 types of protrusive structures in motile cells: lamellipodia (sheet-like) and filopodia (fingerlike) The structure of protrusions is dictated by actin organization Actin dynamics in lamellipodia QuickTime™ and a TIFF decompressor are needed to see this picture. Lamellipodia are composed of branched networks of short actin filaments Actin dynamics in lamellipodia • ARP complex nucleates growth of new filaments • Capping proteins halt growth of filaments to keep them short • Depolymerizing proteins - break down network away from leading edge Filopodia dynamics QuickTime™ and a decompressor are needed to see this picture. http://www.youtube.com/watch?v=VWGA7kIeE0Q Filopodia are composed of long, unbranched, and bundled actin filaments The model for filopodia formation 3. Formation of adhesive contacts with the substrate Cells bind to the ECM (Extra-Cellular Matrix) using transmembrane receptors called integrins Fibronectin Integrins bound to ECM cluster to form “focal adhesions” QuickTime™ and a Photo decompressor are needed to see this picture. Cell Migration Consortium http://www.cellmigration.org/index.shtml Integrins form an indirect linkage between the ECM and actin network • This link to the substrate allows the cell to exert force and gain traction in motility • The amount of tension between the cytoskeleton and the ECM is how cells “feel” the rigidity of their substrate (Durotaxis) The ECM is secreted and maintained by fibroblasts A Cancer cell migrates in vitro through a 3-D collagen matrix QuickTime™ and a Video decompressor are needed to see this picture. Lecaudey, et al., 2008 4. De-adhesion and retraction of the trailing edge • Cells use actin and myosin II to pull on the trailing edge • Myosin II is activated at trailing edge by Rho • When force of tension in the cell is greater than the strength of adhesions, the rear of the cell shortens elastically and contracts further • Old adhesions in the rear are degraded by a calcium-dependent protease called calpain Myosin II is activated at the rear of migrating neutrophils Actin / Myosin II Actin / Rho An exaggerated example of a leading and trailing edge: Fish keratocyte motility Actin QuickTime™ and a MPEG-4 Video decompressor are needed to see this picture. Myosin A model for how forces generated by the actin cytoskeleton move cells forward